Stroke remains a leading cause of mortality and disability, with several thousands of individuals being affected every year in the United States alone. Some degree of spontaneous behavioral recovery occurs during the weeks to months after suffering cortical injury, and one favorable anatomical explanation for this recovery is plasticity of remaining circuits of the ipsilateral-to-lesion hemisphere. It is likely that this neural remodeling varies depending on the locus of injury, but there has been no direct investigation of this possibility. The central hypothesis of this proposal is that spontaneous and training induced plasticity of corticofugal projections vary with the anatomical locus of cortical damage. This will be investigated using a rodent model of upper extremity impairment after ischemic cortical lesions of distinct regions of the motor cortex. The caudal motor cortex (CMC) has been found to posses the capacity to promote rapid recovery of skilled forelimb function after rostral motor cortex (RMC) lesions, but the opposite does not hold true after lesions of the CMC. Whether this is due to the increased capacity for axonal plasticity of corticofugal fibers originating from the CMC has yet to be determined. To investigate the relationship between behavioral outcome and reorganization of cortical efferents, we will assay corticospinal and corticorubral projection patterns after lesions of the CMC and RMC (Aim 1) and determine how this is altered by functionally beneficial (Aim2) and functionally maladaptive (Aim 3) behavioral manipulations. For Aim 1, rats will receive unilateral ischemic lesions of the RMC or CMC and undergo periodic behavioral assessment of paretic forelimb function for one month. Intracortical microstimulation (ICMS) mapping of the ipsilateral-to-lesion cortex will guide injections of biotinylated dextran- amine (BDA), into the spared RMC or CMC depending on the original lesion. Fluorogold (FG) will be injected bilaterally into the C8 spinal cord at the same time. Light and electron microscopy will be used to examine sprouting of spared ipsilateral-to-lesion corticofugal fibers and their synaptic contacts. Skilled motor training can further enhance functional recovery. However, current research has not focused on understanding plasticity of spared descending corticofugal fibers originating in the ipsilateral-to-lesion hemisphere. These axons are the most important for the control of skilled reaching in the normal animal and are likely to contribute to the enhanced motor recovery. Therefore, for Aim 2, the same lesion model will be used as Aim 1, with the addition of animals receiving paretic forelimb rehabilitative motor training (skilled reaching). Finally, Aim 3 will investigate how experience with the non-paretic forelimb influences corticofugal sprouting. Training the non- paretic forelimb worsens paretic forelimb function and contributes to learned non-use. We will investigate whether aberrant plasticity of descending motor fibers originating in the contralateral and/or ipsilesional motor cortex contribute to the adverse affects of non-paretic forelimb training. The proposed research will help elucidate neuroanatomical substrates that promote motor recovery following unilateral cortical infarcts. PUBLIC HEALTH RELEVANCE: The goal of this series of experiments is to understand how neural plasticity of descending motor systems influences functional recovery after brain injury and how behavioral experience further shapes this re-wiring. These studies specifically address how injury-induced plasticity and behavioral manipulations restructure connectivity of existing neural networks to drive functional motor output. This work is pursued to obtain a basal understanding of the anatomical and behavioral substrates that may be targeted in order to facilitate behavioral recovery after brain damage.